Polyketides erythromycin

Peiru, S., Menzella, H.G., Rodriguez, E. et al. (2005) Production of the potent antibacterial polyketide erythromycin C in Escherichia coli. Applied and Environmental Microbiology, 71, 2539. 

Peiru S, Menzella HG, Rodriguez E, Carney J, Gramajo H (2005) Production of the Potent Antibacterial Polyketide Erythromycin C in Escherichia coli. Appl Environ Microbiol 71 2539... 

See also Polyketides, Erythromycin, Oxytetracycline, Fatty Acid Biosynthesis Strategy... 

Long, P.F., Wilkinson, C.J., Bisang, C.P. et al. (2002) Engineering specificity of starter unit selection by the erythromycin-producing polyketide synthase. Molecular Microbiology, 43, 1215. 

Petkovic, H., Lill, R.E., Sheridan, R.M. et al. (2003) A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase. The Journal of Antibiotics, 56, 543. 

Ruan, X., Pereda, A., Stassi, D.L. et al. (1997) Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. Journal of Bacteriology, 179, 6416. 

McDaniel, R., Thamchaipenet, A., Gustafsson, C. et al. (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel unnatural natural products. Proceedings of the National Academy of Sciences of the United States of America, 96, 1846. 

Gokhale, R.S., Hunziker, D., Cane, D.E. and Khosla, C. (1999) Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. Chemistry Biology, 6, 117. 

Roberts, G.A., Staunton, J. and Leadlay, P.F. (1993) Heterologous expression in Escherichia coli of an intact multienzyme component of the erythromycin-producing polyketide synthase. European Journal of Biochemistry, 214, 305. 

There are at least three types of PKS. Type I PKSs catalyze the biosynthesis of macrolides such as erythromycin and rapamycin. As modular enzymes, they contain separate catalytic modules for each reaction catalyzed sequentially in the polyketide biosynthetic pathway. Type II PKSs have only a few active sites on separate polypeptides, and the active sites are used iteratively, catalyzing the biosynthesis of bacterial aromatic polyketides. Type III are fungal PKSs they are hybrids of type I and type II PKSs [49,50]. 

Kosan Biosciences was formed almost 6 years ago, founded on an interest in polyketides, microbial metabolite-based drugs. Polyketides have many diverse chemical structures including erythromycin, which will be mentioned again later. These chemicals include fused-ring aromatic compounds, compounds decorated with sugars, and compounds with large stretches of double bonds. Each of these compounds has different biological activities and utilities, but they are all made in nature by very similar biochemistry. 

The polyketides are a large family of bio synthetically related NPs, some of which have very great pharmaceutical value (polyketide sales total about 10 billion annually, see also Chapter 7). Some antibiotics (erythromycin, monensin, rifamycin), immunosuppressants (rapamycin), antifungal substances (amphotericin), antiparasitic (aver-mectin) and anticancer drugs (doxorubicin) are polyketides. The term polyketide refers to the fact that the basic carbon skeleton is not a simple hydrocarbon chain as in the case of fatty acids but is a series of linked keto groups in sequence (Figure 3.6). The first phase of this pathway, the generation of carbon skeleton diversification. 

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

J Cortes, SH Haydock, GA Roberts, DJ Bevitt, PF Leadlay. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 348 176-178, 1990. 

DJ Bevitt, J Staunton, PF Leadlay. Mutagenesis of the dehydratase active site in the erythromycin-producing polyketide synthase. Biochem Soc Trans 21 30S, 1992. 

Figure 2 Examples of polyketides. Polyketides demonstrate a broad range of biological activities, including antibiotic (oxytetracycline and erythromycin), antitumor (doxorubicin and dynemicin), antiparasitic (avermectin), and immunosuppressive (FK506). Monensin is used as a bovine feed supplement and an anticoccidial agent.

B. Erythromycin, Rapamycin, and Other Modular Polyketide Synthases... 

Finally, the potential number of compounds that could theoretically be produced by a modular PKS if all aspects of structural diversity could be controlled is enormous. For example, a six-module PKS, such as the erythromycin PKS, has a theoretical potential of tens of thousands of compounds. This number increases exponentially as the number of modules increases. While the theoretical number of polyketides may never be achieved, the possibility of generating even a small... 

R Pieper, G Luo, DE Cane, C Khosla. Cell-free biosynthesis of polyketides by recombinant erythromycin polyketide synthases. Nature 378 263-266, 1995. 

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